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Drug Metabolism & Disposition

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Abstract

Clinical pharmacology of 1-beta-D-arabinofuranosyl-5-azacytosine (fazarabine) following 72-hour infusion.

D H Ho, N Brown, J R Lin, W Covington, R A Newman, M Raber, R Amato, S Schmidt and I H Krakoff
Drug Metabolism and Disposition May 1991, 19 (3) 643-647;
D H Ho
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N Brown
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J R Lin
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W Covington
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R A Newman
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M Raber
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R Amato
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S Schmidt
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I H Krakoff
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Abstract

The clinical pharmacology of fazarabine (1-beta-D-arabinofuranosyl-5-azacytosine), a structural analogue of 1-beta-D-arabinofuranosylcytosine (ara-C) and 5-azacytidine, was assessed in 14 patients with various malignancies during a phase I trial. Since the starting dose for the protocol was low (0.2 mg/m2/hr over a 72-hr continuous iv infusion), a radioimmunoassay (RIA) using commercially available ara-C antibody and [3H]ara-C was developed to measure the anticipated low plasma drug levels. The assay could be used to measure fazarabine accurately in plasma and urine with a sensitivity of 0.08 ng/ml. The RIA does not require extraction of samples. Using both RIA and HPLC, similar results were obtained in plasma samples from a patient receiving a high dose (180 mg/m2/hr) of fazarabine. The assay is simple, sensitive, reproducible, and specific. Following the infusion, plasma levels declined triphasically with a terminal half-life of 5.7 +/- 2.0 hr. The AUC was linearly related to dose. When the various doses were normalized to 1.75 mg/m2/hr (the maximum tolerated dose as determined from the phase I trial) the mean AUC value was 4232 +/- 987 (ng/ml)hr. Plasma steady-state drug levels (CPss) were achieved in 2-4 hr and were linearly dependent to dose. Also, when normalized, the mean CPss was 58 +/- 13 ng/ml, which is within the reported concentration range necessary for inhibiting malignant cell growth. Total clearance was rapid, 528 +/- 138 ml/(m2.min), and not dose-related.

 

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Drug Metabolism and Disposition
Vol. 19, Issue 3
1 May 1991
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Abstract

Clinical pharmacology of 1-beta-D-arabinofuranosyl-5-azacytosine (fazarabine) following 72-hour infusion.

D H Ho, N Brown, J R Lin, W Covington, R A Newman, M Raber, R Amato, S Schmidt and I H Krakoff
Drug Metabolism and Disposition May 1, 1991, 19 (3) 643-647;

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Abstract

Clinical pharmacology of 1-beta-D-arabinofuranosyl-5-azacytosine (fazarabine) following 72-hour infusion.

D H Ho, N Brown, J R Lin, W Covington, R A Newman, M Raber, R Amato, S Schmidt and I H Krakoff
Drug Metabolism and Disposition May 1, 1991, 19 (3) 643-647;
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